Laser ablation therapy has been used to treat pre-malignant lesions of the esophagus with the goal of preventing progression to adenocarcinoma. Existing laser ablation approaches, however, lack the precision necessary to target only the pathologic tissue while sparing neighboring healthy tissue, resulting in significant complications and reduced efficacy. The research focus of this K25 application is to develop and test in vivo a novel endoscopic laser therapy system capable of conforming local therapy to in situ measurements of local anatomy and physiology. The breadth of this research will provide an outstanding contextual training experience, highlighting the methods and conduct of biomedical and clinical research that will complement the candidate's existing expertise in physics and optical technologies. The research training component will occur within the Wellman Center for Photomedicine at the Massachusetts General Hospital under the primary mentorship of Dr. Bouma, a leader in the field of biomedical optics and translational clinical research. Research will initially focus on the in vitro testing of the system capabilities, which will provide training in the methods and interpretation of histopathology as well as the handling of biological tissues. Subsequent in vivo studies of the technical capabilities and safety of the system will provide training in the ethics and conduct of live animal and human studies. Complementary coursework offered at the Harvard Medical School and the Harvard-MIT Division of Health Sciences and Technology will enable the candidate to develop a solid background in cancer biology, cancer treatment, and biostatistics. The training and preliminary data provided in this proposal will enable the candidate to prepare applications for funding that will enable a transition to independent research focusing on the translation of novel technologies to clinical practice. The immediate focus of the proposed research is to develop new methods capable of precise and comprehensive treatment of esophageal pathology prior to the onset of adenocarcinoma. Since esophageal adenocarcinoma is a prevalent disease associated with high morbidity and dismal survival, an improved therapeutic approach that addresses the shortcomings of currently available therapies will make a significant impact.